The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
Replacement Dose, Metabolism, and Bioavailability of Levothyroxine in the Treatment of Hypothyroidism
Abstract
A change in the formulation of the levothyroxine preparation Synthroid (Flint) in 1982 prompted us to reevaluate the replacement dose of this drug in 19 patients with hypothyroidism. The dose was titrated monthly until thyrotropin levels became normal. The mean replacement dose (+/- SD) was 112 +/- 19 micrograms per day, significantly less (P less than 0.001) than the dose of an earlier formulation--169 +/- 66 micrograms per day--used in a similar study (Stock JM, et al. N Engl J Med 1974; 290:529-33). The fractional gastrointestinal absorption of a tablet of the current formulation is 81 percent, considerably higher than the earlier estimate of 48 percent. Using high-performance liquid chromatographic analysis, we found that the current tablet contains the amount of thyroxine stated by the manufacturer. By measuring the bioavailability of the earlier type of tablet in five patients, we inferred that the strength of the previous tablet had been overestimated. In the present study, the thyrotropin levels of patients on replacement therapy returned to normal when serum triiodothyronine concentrations were not significantly different from those of controls (122 vs. 115 ng per deciliter [1.87 vs. 1.77 nmol per liter]), but when serum thyroxine levels were significantly above those of controls (11.3 vs. 8.7 micrograms per deciliter [145 vs. 112 nmol per liter], P less than 0.001). These findings suggest the possibility that in humans, serum triiodothyronine may play a more important part than serum thyroxine in regulating the serum thyrotropin concentration.
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In the citing paper
“The absorption of an orally administered dose of LT4 is about 70%-80% under optimum fasting conditions (38,119,120).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“Steady-state levels of T4 and TSHaregenerally achieved in 6 weeks (approximately five to six half-lives) after initiation of therapy (38).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“Moreover, in athyreotic individuals treated with LT4 to achieve a normal serum TSH, the serum FT4 is usually higher and the serum T3 is either normal (38,39) or lower than the values seen in normal individuals (39-43).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“Based on body weight, hypothyroid patients with minimal endogenous thyroid function require LT4 doses of 1.6-1.8 l g/kg of actual body weight (38,47,212,213,215-217,226,227), although some studies estimate higher doses of 2.0-2.1 l g/kg for some patient groups (212,213,226).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“LT4 doses in thyroid cancer patients requiring TSH suppression are generally higher and on the order of 2.1-2.7 l g/kg (38,212,215).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [38]
In the citing paper
“The peripheral conversion of T4 into T3 makes it possible to achieve normal serum T3 concentrations in humans treated with L-T4 [26] ,”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [26]
In the citing paper
“Normalization of serum TSH and T3 concentrations is achieved with L-T4 therapy at the expense of higher serum free T4 concentrations than normal [26,27] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [26]
In the citing paper
“To obtain serum TSH values similar to controls during L-T4 monotherapy, serum free T4 concentrations higher than controls are required at serum free T3 values similar to those in controls [26,27] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [26]
In the citing paper
“As a consequence, in daily clinical practice mental health providers in community settings do not ask about medical issues or test for them because of insufficient consideration of the physical health needs, or shortage or time/ resources.315”
From The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness (2019) · cites this paper as [315]
In the citing paper
“In a previous study involving 19 patients, the TSH levels were normalized only when patients’ T3 levels were not significantly different from those of controls (159).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [159]
In the citing paper
“While earlier studies already hinted that TSH normalization may not suffice to guarantee a normal serum T3, the more detailed inter-relationships have only recently been analyzed (9, 122, 196–199).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [196]
Citations
Cites
Thyroid-Pituitary Interaction: Feedback Regulation of Thyrotropin Secretion by Thyroid Hormones
Bleich, H. L., Moore, M. J., & Larsen, P. R. (1982) · New England Journal of Medicine · doi:10.1056/nejm198201073060107 · Cited by 357
Oppenheimer, J. H., Squee, R., Surks, M. I., & Hauer, H. (1963) · Journal of Clinical Investigation · doi:10.1172/jci104862 · Cited by 255
Surks, M. I., Schadlow, A. R., Stock, J. M., & Oppenheimer, J. H. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107244 · Cited by 223
SILVA, J. E., DICK, T. E., & LARSEN, P. R. (1978) · Endocrinology · doi:10.1210/endo-103-4-1196 · Cited by 189
Surks, M. I., Schadlow, A. R., & Oppenheimer, J. H. (1972) · Journal of Clinical Investigation · doi:10.1172/jci107137 · Cited by 188
Replacement Dosage of L-Thyroxine in Hypothyroidism: A Re-Evaluation
Stock, J. M., Surks, M. I., & Oppenheimer, J. H. (1974) · New England Journal of Medicine · doi:10.1056/nejm197403072901001 · Cited by 184
Self-citationAutoantibodies Against Thyroid Hormones or lodothyronine
Sakata, S., NAKAMURA, S., & MIURA, K. (1985) · Annals of Internal Medicine · doi:10.7326/0003-4819-103-4-579 · Cited by 174
Pulsatile secretion of thyrotropin in man
GREENSPAN, S. L., KLIBANSK, A., SCHQENFELD, D., & RIDGWAY, E. C. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-3-661 · Cited by 140
Oppenheimer, J. H., Schwartz, H. L., & Surks, M. I. (1975) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-41-2-319 · Cited by 137
CIRCADIAN VARIATIONS OF SERUM THYROTROPIN LEVELS IN MAN1
Vanhaelst, L., Cauter, E. V., Degaute, J. P., & GOLSTEIN, J. (1972) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-35-3-479 · Cited by 118
Research works printed but not linked: 1
- Jacobus R, Rabinow B, Luecke J. Determination of levothyroxine sodium in the drug substance and Synthroid levothyroxine sodium tablets by reverse-phase high-performance liquid chromatography. In: Proceedings of the FDA-USP workshop on drug and reference standards for insulins, somatotropins and thyroid-axis hormones. Bethesda, Md.: U.S. Pharmacopeial Convention, 1982:487–95.
Cited by
Sorted by citations
Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., et al. (2014) · Thyroid® · doi:10.1089/thy.2014.0028 · Cited by 1,928
“Steady-state levels of T4 and TSH are generally achieved in 6 weeks (approximately five to six half-lives) after initiation of therapy (38).”
InfluentialFirth, J., Siddiqi, N., Koyanagi, A., Siskind, D., Rosenbaum, S., Galletly, C., Allan, S., Caneo, C., Carney, R., Carvalho, A. F., et al. (2019) · The Lancet Psychiatry · doi:10.1016/s2215-0366(19)30132-4 · Cited by 1,531
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber, K. A. (2012) · Endocrine Practice · doi:10.4158/ep12280.gl · Cited by 1,567
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber for the American Association, K. A. (2012) · Thyroid · doi:10.1089/thy.2012.0205 · Cited by 1,053
Léger, J., Olivieri, A., Donaldson, M., Torresani, T., Krude, H., van Vliet, G., Polak, M., Butler, G., & on behalf of ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE, A. T. C. H. C. C. G. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1891 · Cited by 569
Metadata
- Authors
- Fish, L. H., Schwartz, H. L., Cavanaugh, J., Steffes, M. W., Bantle, J. P., & Oppenheimer, J. H.
- ORCID
- Steffes, Michael W.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1987-03-26
- Volume
- 316
- Issue
- 13
- Pages
- 764-770
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2324164337
- Cited by
- 353
- References
- 18
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 13 · 2017: 14 · 2016: 19 · 2015: 13 · 2014: 13 · 2013: 9 · 2012: 17
- FWCI
- 11.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AM-19-812, 2t32am007203-09, 1f32am007586-01)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- levothyroxine, hypothyroidism, drug formulation change, bioavailability, gastrointestinal absorption, drug metabolism, thyroid-stimulating hormone, serum triiodothyronine, serum thyroxine, dose titration
- MeSH terms
- Biological Availability, Feedback, Humans, Hypothyroidism, Intestinal Absorption, Pituitary Gland, Anterior, Tablets, Thyrotropin, Thyroxine, Triiodothyronine
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